Busulfan-fludarabine versus busulfan-cyclophosphamide for allogeneic transplant in acute myeloid leukemia: long term analysis of GITMO AML-R2 trial.

We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40-65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches.

Real-world treatments and clinical outcomes in unfit AML patients receiving first-line treatment or best supportive care in Italy (CURRENT study).

Real-world data on treatment patterns and outcomes of patients with acute myeloid leukemia unfit for intensive chemotherapy are lacking before the advent of precision medicine in this setting. Herein, we present the Italian sub-analysis of the CURRENT study in AML patients unfit for first line intensive chemotherapy, evaluating patients' outcomes between 2015 and 2018. Among 74 evaluable patients, 62 received systemic treatments (most used therapy was hypomethylating agents), while 12 best supportive care. Key results include both efficacy and safety data, as well as HCRU and treatment patterns. In first-line therapy cohort median OS was 13.4 months vs. 2.7 months for BSC.

Evaluation of Circulating Endothelial Cells as Direct Marker of Endothelial Damage in Allo-Transplant Recipients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome.

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a rare but potentially fatal complication following allogenic hematopoietic cell transplantation (allo-HCT). Timely identification of SOS/VOD to allow for prompt treatment is critical, but identifying a VOD-predictive biomarker remains challenging. Given the pivotal role of endothelial dysfunction in SOS/VOD pathophysiology, the CECinVOD study prospectively evaluated levels of circulating endothelial cells (CECs) in patients undergoing allo-HCT with a myeloablative conditioning (MAC) regimen to investigate the potential of CEC level in predicting and diagnosing SOS/VOD. A total of 150 patients from 11 Italian bone marrow transplantation units were enrolled. All participants were age >18 years and received a MAC regimen, putting them at elevated risk of developing SOS/VOD. Overall, 6 cases of SOS/VOD (4%) were recorded. CECs were detected using the Food and Drug Administration-approved CellSearch system, an immunomagnetic selection-based platform incorporating ferrofluid nanoparticles and fluorescent-labeled antibodies, and were defined as CD146+, CD105+, DAPI+, or CD45-. Blood samples were collected at the following time points: before (T0) and at the end of conditioning treatment (T1), at neutrophil engraftment (T2), and at 7 to 10 days postengraftment (T3). For patients who developed VOD, additional samples were collected at any suspected or proven VOD onset (T4) and weekly during defibrotide treatment (T5 to T8). A baseline CEC count >17/mL was associated with an elevated risk of SOS/VOD (P = .04), along with bilirubin level >1.5 mg/mL and a haploidentical donor hematopoietic stem cell source. Postconditioning regimen (T1) CEC levels were elevated (P = .02), and levels were further increased at engraftment (P < .0001). Additionally, patients developing SOS/VOD after engraftment, especially those with late-onset SOS/VOD, showed a markedly higher relative increase (>150%) in CEC count. Multivariate analysis supported these findings, along with a high Endothelial Activation and Stress Index (EASIX) score at engraftment (T2). Finally, CEC kinetics corresponded with defibrotide treatment. After the start of therapy (T4), CEC levels showed an initial increase in the first week (T5), followed by a progressive decrease during VOD treatment (T6 and T7) and a return to pre-SOS/VOD onset levels at resolution of the complication. This prospective multicenter study reveals a low incidence of SOS/VOD in high-risk patients compared to historical data, in line with recent reports. The results from the CECinVOD study collectively confirm the endothelial injury in allo-HCT and its role in in the development of SOS/VOD, suggesting that CEC level can be a valuable biomarker for diagnosing SOS/VOD and identifying patients at greater risk of this complication, especially late-onset SOS/VOD. Furthermore, CEC kinetics may support treatment strategies by providing insight into the optimal timing for discontinuing defibrotide treatment.

Uncommon Presentation of Sarcoidosis with Severe Thrombocytopenia and Hemorrhagic Diathesis.

Sarcoidosis, a multi-organ system disease, often presents insidiously. Thrombocytopenia in sarcoidosis is frequent because of hypersplenism, granulomas infiltrating the bone marrow, or immune thrombocytopenia (ITP). The diagnosis of ITP relies on exclusionary criteria, given the absence of a definitive laboratory diagnostic feature. In the era prior to modern ITP management, sarcoidosis-associated ITP was known to manifest severely, often showing resistance to treatment and an increased risk of mortality. In this case, we present a young male who was admitted to a district hospital's emergency room, displaying symptoms of hematuria, gingival bleeding, and a petechial rash. Blood tests revealed severe thrombocytopenia with a platelet count of 0, while all other metabolic and serological exams returned normal results. Infectious and autoimmune causes were ruled out, and a bone marrow examination excluded any hematological disorder. Initial management, including platelet transfusion and presumptive treatment for ITP with dexamethasone and Human Immunoglobulin IV (IVIG), failed to improve the patient's platelet count or alleviate the hemorrhagic diathesis. Second-line therapy with Rituximab and Methylprednisolone was initiated with no benefit. Considering the hemorrhagic signs and the delayed response of Rituximab, we shifted to third-line therapy with Romiplostim at the maximal dose and continued Methylprednisolone. The platelet count recovered completely after the second Romiplostim administration (over 350 × 109 platelets/L) and Methylprednisolone was rapidly tapered. To further study the causes of thrombocytopenia a total body CT scan was performed and it identified non-homogeneously hypodense tissue in the bilateral hilar area extending medially to the subcarinal area, suggesting possible lymphatic origin and raising suspicion of sarcoidosis. Further investigations, including Angiotensin Converting Enzyme (ACE) titration, bronchoscopy, bronchoalveolar lavage, and EndoBronchial UltraSound-guided TransBronchial Needle Aspiration (EBUS-TBNA), confirmed the diagnosis of sarcoidosis. Despite a mild restrictive insufficiency noted in spirometry, the patient remained asymptomatic with only a mild respiratory insufficiency, and hence, was enlisted for follow-up. As for the ITP, the platelet count remained normal over a year. Notably, while sarcoidosis onset often predates ITP onset by an average of 48 months, in our case the onset of the two diseases was simultaneously. Our case adds valuable information to the limited body of knowledge regarding the treatment of sarcoidosis-associated ITP.

Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights.

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd-Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.

Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort.

VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.

The role of hematopoietic stem cell transplantation in the elderly patient with acute myeloid leukaemia / O papel do transplante de célula-tronco hematopoiética em pacientes idosos com leucemia mielóide aguda

Older adults with Acute Myeloid Leukaemia (AML), when compared to younger patients with the same disease, have a poor prognosis and represent a discrete population in terms of disease biology, treatment-related complications, and overall outcome. As a result, older patients require distinctive management approaches. For 85 percent-95 percent of older AML patients, any therapy ultimately will be purely palliative. No randomized trial has ever demonstrated that any amount of post-remission therapy in older AML patients provides better outcomes than no post-remission therapy. The only studies demonstrating that long-term Disease Free Survival (DFS) is possible in older AML patients have included remission induction and post-remission therapy. For these reasons alternative post-remission strategies, including autologous or allogeneic transplantation have been explored also in people over sixty considered fit for aggressive therapy. Up to now the data available from clinical trials suggest that the stem cell transplant procedure is promising, and can lead to long-term survival, but it is feasible only in a minority of fit elderly patients. The main limits of Autologous Stem Cell Transplantation (ASCT) are represented by the low percentage of patients able to mobilize a sufficient amount of stem cells and by the still high relapse incidence after ASCT, especially in those with poor prognostic factors; for these patients the allogeneic transplant procedure, by using non myeloablative conditioning regimens, could offer a better chance of cure, thanks to the Graft versus Leukemia (GVL) effect, but there are no prospective trials showing the superiority of any transplant approach over conventional treatment in this subset of patients.

Pacientes idosos com leucemia mielóide aguda (LMA), quando comparados com pacientes jovens com a mesma doença, apresentam prognóstico pobre e representam uma população particular em termos biológicos, complicações relacionadas ao tratamento e evolução clínica. Como resultado de tudo isto, o paciente idoso requer manuseio distinto. Para 85 por cento-95 por cento dos pacientes idosos a abordagem terapêutica será finalmente apenas paliativa. Nenhum estudo randomizado demonstrou qualquer vantagem de qualquer terapêutica na fase pós-remissão. Os únicos estudos que mostraram alguma vantagem em termos de sobrevida livre de doença em pacientes idosos portadores de LMA incluíram juntas as fases de indução e consolidação da remissão. Por estas razões, estratégias terapêuticas alternativas pós-remissão, incluindo transplante autólogo ou alogênico, têm sido exploradoras também em pacientes acima de 60 anos com boa performance status para as terapias de alta dose. Até agora, os dados disponíveis dos estudos clínicos sugerem que o procedimento usando célula-tronco é promissor e pode levar a sobrevida de longo prazo, porém factível apenas em uma minoria de pacientes idosos. Os principais limites para o transplante autólogo são representados pela baixa porcentagem de pacientes capazes de mobilizar suficiente quantidade de células-tronco e pela, ainda, alta incidência de recidiva após o transplante, principalmente em pacientes de fatores de mau prognóstico. Para o transplante alogênico, o uso de regimes de intensidade reduzida pode oferecer uma melhor oportunidade de cura graças ao efeito enxerto versus leucemia. Porém, não existem estudos clínicos comprovando a superioridade de qualquer modalidade de transplante em relação à terapia convencional.

Células-tronco mesenquimal: uso potencial em transplante, expansão e aplicações clínicas / Mesenchymal stem cells: transplantation potential, expansion and clinical applications

As células-tronco mesenquimais podem ser isoladas da medula óssea, sangue de cordão umbilical, tecido adiposo, derme, músculos e são capazes de diferenciação e reconstituição de inúmeros tecidos. Nesta pequena revisão são discutidos aspectos relacionados com o possível potencial no transplante e em outras aplicações clínicas das células-tronco mesenquimais. São discutidos os critérios que devem ser observados nos estudos e sumarizados os resultados e as perspectivas dos ensaios já realizados com as células-tronco mesenquimais.

Mesenchymal stem cells are a human stem cells isolated from bone marrow, umbilical cord blood, adipose tissues dermis and muscles and are capable to differentiation and reconstitution of many tissues. In this short review I discuss many features about the potential transplant and clinical applications of MSC. I also discuss the criterias for the applications and summarize the results and perspectives of the clinical trials with MSC.